title: IL-33 is more potent than IL-25 in provoking IL-13-producing nuocytes (type 2 innate lymphoid cells) and airway contraction.
abstract: BACKGROUND
  IL-25 and IL-33 belong to distinct cytokine families, but experimental mouse studies suggest their immunologic functions in type 2 immunity are almost entirely overlapping. However, only polymorphisms in the IL-33 pathway (IL1RL1 and IL33) have been significantly associated with asthma in large-cohort genome-wide association studies.
  
  
  OBJECTIVE
  We sought to identify distinct pathways for IL-25 and IL-33 in the lung that might provide insight into their roles in asthma pathogenesis and potential for therapeutic intervention.
  
  
  METHODS
  IL-25 receptor-deficient (Il17rb(-/-)), IL-33 receptor-deficient (ST2, Il1rl1(-/-)), and double-deficient (Il17rb(-/-)Il1rl1(-/-)) mice were analyzed in models of allergic asthma. Microarrays, an ex vivo lung slice airway contraction model, and Il13(+/eGFP) mice were then used to identify specific effects of IL-25 and IL-33 administration.
  
  
  RESULTS
  Comparison of IL-25 and IL-33 pathway-deficient mice demonstrates that IL-33 signaling plays a more important in vivo role in airways hyperreactivity than IL-25. Furthermore, methacholine-induced airway contraction ex vivo increases after treatment with IL-33 but not IL-25. This is dependent on expression of the IL-33 receptor and type 2 cytokines. Confocal studies with Il13(+/eGFP) mice show that IL-33 more potently induces expansion of IL-13-producing type 2 innate lymphoid cells, correlating with airway contraction. This predominance of IL-33 activity is enforced in vivo because IL-33 is more rapidly expressed and released in comparison with IL-25.
  
  
  CONCLUSIONS
  Our data demonstrate that IL-33 plays a critical role in the rapid induction of airway contraction by stimulating the prompt expansion of IL-13-producing type 2 innate lymphoid cells, whereas IL-25-induced responses are slower and less potent.
authors.affiliation: Medical Research Council Laboratory of Molecular Biology, Hills Road, Cambridge, United Kingdom. Electronic address: jbarlow@mrc-lmb.cam.ac.uk.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Barlow
authors.forename: Samantha
authors.initials: S
authors.lastname: Peel
authors.forename: Jane
authors.initials: J
authors.lastname: Fox
authors.forename: Veera
authors.initials: V
authors.lastname: Panova
authors.forename: Clare S
authors.initials: CS
authors.lastname: Hardman
authors.forename: Ana
authors.initials: A
authors.lastname: Camelo
authors.forename: Christine
authors.initials: C
authors.lastname: Bucks
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Wu
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Kane
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Neill
authors.forename: Robin J
authors.initials: RJ
authors.lastname: Flynn
authors.forename: Ian
authors.initials: I
authors.lastname: Sayers
authors.forename: Ian P
authors.initials: IP
authors.lastname: Hall
authors.forename: Andrew N J
authors.initials: AN
authors.lastname: McKenzie
mesh_terms: D000818:Animals; D001249:Asthma / Q000276:immunology / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000503:physiopathology; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis*; D000067596:Interleukin-33; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
chemical_list: C506535:Il33 protein, mouse; D018793:Interleukin-13; D000067596:Interleukin-33; D007378:Interleukins; C442281:Mydgf protein, mouse
keywords: AHR; Airways hyperreactivity; BAL; Bronchoalveolar lavage; Cit; Citrine; ICOS; IL-13; IL-25; IL-33; ILC2; Inducible costimulator; Nuocytes; OVA; Ovalbumin; RWP; Ragweed pollen; Tom; Tomato; Type 2 innate lymphoid cells; asthma; contraction; type 2 innate lymphoid cells